CARDINNATE: Variation in innate immune activation and cardiovascular disease risk as drivers of COVID19 outcome in South Asians in UK and India

While COVID-19 causes minor illness in most people, some individuals develop more severe disease requiring admission to hospital including intensive care. People of South Asian heritage admitted with severe COVID-19 in the UK have a higher death rate than those of other ethnic backgrounds even after adjusting for their age or socioeconomic status. However, death rates for South Asians with COVID-19 appear to be much lower in India than the UK. This is very surprising given that the health service in India is less comprehensive than the national health service and in India the average socioeconomic conditions are significantly lower than the UK. This unexpected disparity between countries suggests that factors beyond socioeconomic conditions per se are important in determining whether people survive severe COVID-19.

Our understanding of immune priming and activation leads us to propose that biological factors that regulate how the body responds to infection may be very important. The body's immune system is vital in fighting infection. We know that severe COVID-19 is associated with profound abnormalities of the immune response. Furthermore, severe COVID-19 is accompanied by life-threatening problems with heart and blood vessel function. We propose that differences in immune response and how this impacts on heart and blood vessel function may contribute to the effects of COVID-19 on South Asians in the UK and India. One possibility is that the immune system of people in India is better trained to respond to infection because of continued exposure to a variety of infections and environmental factors that are uncommon in the UK. A poorer immune response to infection in South Asians in the UK combined with their high underlying rates of diabetes and heart disease may result in worse disease and life threatening complications when they get COVID-19. Such biological factors may therefore account for the disproportionate effects of COVID-19 in South Asians in UK.

We have put together an expert interdisciplinary team of scientists and medical doctors from the UK and India who have outstanding experience in infectious diseases, immunology, heart and blood vessel disorders, and intensive care. Our team will work together to drill down into the problem and prove exactly why COVID-19 affects South Asians in different countries in different ways. We aim to rapidly identify information that allows us to develop new prevention steps, more targeted monitoring, and hopefully new treatments to improve the outcome of COVID-19 in both India and the UK.

In the UK, individuals of South Asian heritage have a higher COVID-19 mortality rate than other ethnic groups, even after adjusting for age and social factors. This is driven by a greater risk of in-hospital death rather than an increased rate of admissions, in part related to a higher prevalence of cardiovascular disease (CVD) and diabetes which are recognised risk factors for severe COVID-19. By contrast, mortality rates for COVID-19 in India are markedly lower than the UK.
Severe COVID-19 is associated with profound systemic immune dysregulation, haemodynamic and thrombotic complications. Multiple lines of evidence suggest that innate immune mechanisms, specifically variation in the regulation of the type 1 interferon (IFN) response and the subsequent dysregulation of cellular innate and adaptive immunity, may be very important determining factors in COVID-19 pathogenesis. Hence these mechanisms are good candidates for underlying increased mortality risk in UK South Asians and set a platform for understanding why the situation is different in India.
Our multi-disciplinary UK and India team will elucidate the inter-relationship among innate immune mechanisms, pre-existing CVD/diabetes and environment (India versus UK). Differences in innate immunity, which provides a first line of defence to infection, are captured by the term "trained immunity", reflecting its conditioning in part via IFN, by exposure to endemic environmental pathogens, diet, and inflammatory conditions including CVD/diabetes. Hence, evident differences in these factors for South Asians in India versus the UK may profoundly affect the speed and strength of first-phase immune responses to SARS CoV2, as well as attendant cardiovascular damage and dysfunction, to collectively drive systemic immunopathology and the differences in COVID-19 mortality between the UK and India.